DESCRIPTION: Pulmonary arterial hypertension is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary vasculature and the right heart. Recently studies from others and our own suggested that disruption of the metabolic signaling pathway such as mitochondrial abnormalities contribute to the pathogenesis of PAH and constitute promising therapeutic targets. It is also becoming clear that epigenetic regulation plays an important role in the manifestation of lung vascular disease including PAH. Recently technologies have emerged to examine the control of transcription including epigenetic modifications at genome-wide level. Given the unique opportunity this RFA provides, the goal of this exploratory study is to identify genome-wide methylation (GWM) profiles from across the epigenome that contribute to PAH pathogenesis. We hypothesize that 1) epigenetic modification in GWM profiles plays a major role in the regulation of gene expression and is associated with altered risk of PAH and 2) disruption of metabolic signaling such as mitochondrial abnormalities represents the unifying cause for PAH. To test this hypothesis, we intend to (1) compare GWM profiles in IPAH cases and non-disease controls from >450,000 methylation sites in the human genome, using the Illumina Methyl450K analysis, and compare GWM profiles obtained from lung tissue and peripheral blood to validate blood-source DNA as surrogate tissue; (2) define the contribution of epigenetic pathways to the global regulation of gene expression; and (3) validate targets from GWM profiles and gene expression profiling including metabolic signaling pathway molecules as biomarkers using serum and lung tissue samples from patients with PAH. If successful, our proposed research will provide mechanistic insights into epigenetic targeting and can be used to develop tools to reverse specific disease-causing, aberrant epigenetic changes as a potential novel therapeutic approach for PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a lethal syndrome characterized by vascular obstruction and right ventricular failure. It is becoming clear that epigenetic regulation plays an important role in the manifestation of lung vascular disease including PAH. In this study, we will utilize integrative unbiased genome-wide approaches to determine the distinct genome-wide methylation and gene expression signatures in PAH patients compared to non-disease control subjects and validate metabolic signaling pathway molecules as biomarkers and novel therapeutic targets for PAH therapy. (End of Abstract)